Background: Venous thromboembolism (VTE) strikes 1-2/1000 Americans annually, and is a common cause of cardiovascular death. The etiology of VTE is multi-factorial, with both genetic and environmental factors contributing to incidence. However, known genetic and environmental risk factors explain less than 50% of VTE incidence and genome-wide association studies (GWAS) have been unsuccessful in identifying novel loci. Little is known about possible gene-environment interactions. Setting: This study will be performed by an experienced, multidisciplinary, multi-institutional group of thromboembolism researchers, genetic and cardiovascular epidemiologists, and experts in statistical genetics working at Harvard University and the Mayo Clinic. Investigators on this project have decades of experience conducting genetic and epidemiological studies, and have published hundreds of peer reviewed papers relevant to the current proposal. Research Plan: We will examine data from the Nurses' Health Studies I & II (NHS I&II) and the Health Professionals Follow Up (HPFS) study. NHS I&II and HPFS are ongoing prospective cohort studies of 121,700 and 116,686 female nurses, and 51,529 male health professionals. For each of the three cohorts, data describing VTE and prospective environmental exposures have been collected for more than 25 years. We will perform the first exome wide association study (XWAS) of VTE in 2,500 VTE cases and 2,500 controls, using the newly available Illumina(R) HumanExome BeadChip that includes 220,000 coding genetic variants to a population prevalence of 0.005%. We will replicate our top XWAS findings in an independent clinic-based sample of 2000 VTE cases and 2000 controls from the Mayo Clinic. Additionally, we will include custom content on the exome chip to perform deep replication of the top 5,000 single nucleotide polymorphisms (SNPs) identified in two previously completed VTE GWAS. Lastly, we will study interactions between confirmed genetic polymorphisms and four key environmental risk factors for VTE identified in our prior work: obesity, physical inactivity, smoking, and postmenopausal hormone use. Relevance to Public Health: VTE is a common and deadly disease, a fact highlighted by the Acting Surgeon General of the United States who in 2008 issued a 'Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism' urging more research on the causes, prevention, and treatment of deep vein thrombosis. The current proposal will be the most comprehensive assessment of genetic and environmental risk factors for VTE to date, will provide insight into the basic pathophysiology of VTE and has the potential to impact clinical practice. Our approach is both innovative and is cost-effective as it builds on decades of prospective data collection from three large cohorts and existing data. Our analyses will result in identification of novel common genetic loci for VTE. Given the high population prevalence of risk factors and the high mortality of VTE, the potential public health impact of this work is large.